Many therapeutic molecules are polypeptides, some of which are prone to denaturation, degradation, and/or aggregation. Aggregation of polypeptides is undesirable as it may result in immunogenicity (Cleland et al., 1993, Crit. Rev Therapeutic Drug Carrier Systems, 10: 307-377; and Robbins et al., 1987, Diabetes, 36: 838-845). Polypeptides are also subject to catalysis or conversion into inactive forms by the natural biological processes of the organisms to which they are administered. Further, therapeutic polypeptides may be produced as a heterogeneous mixture of forms, varying in the extent of glycosylation or in other aspects of their three-dimensional conformation.
Crystallization of therapeutic polypeptides provides an advantage in producing a stable and homogenous formulation of such polypeptides. Certain advantages of crystals include greater ease of handling of the therapeutic compound in preparing pharmaceutical products; reduced degradation, denaturation and/or aggregation; the potential for creating a sustained release form of the therapeutic polypeptide to reduce the frequency of dosing; and the ability to use crystalline therapeutic polypeptides to form a pharmaceutical composition having a very high concentration of the therapeutic polypeptide. In addition, crystallization methods can produce a more homogenous population of polypeptides in the formulation, because only the addition of similarly configured polypeptide molecules will add to sustained growth of the crystal—when a limiting amount of polypeptides of variant structure have been incorporated into the crystal lattice, the resulting structural weaknesses in the crystal will prevent its further growth. Since incorporation into a crystalline form can ensure that a greater percentage of the polypeptides will be in an active form, administration of a smaller amount of the crystalline therapeutic peptides can produce a therapeutic effect equivalent to administration of a greater amount of a more heterogeneous polypeptide formulation.
Therefore, there is a need for crystalline formulations of therapeutic polypeptides.